JPH11228573A - Indole compound, its production method and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel indole compound having a physiological activity such as a lipid peroxidation inhibitory activity and a method for synthesizing the same. SOLUTION: The indole compound represented by the following formula (1). Embedded image [In the formula, R represents a hydrogen atom, alkyl, aralkyl, cycloalkyl, aryl, monovalent metal atom, amine or ammonium. The above compound is produced by a synthesis method in which an amide is formed by condensation of tryptophan and 4-methylhexanoic acid, and then an oxazole ring is formed at once by an oxidative cyclization reaction of the amide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel indole compound or a salt thereof, a method for producing the compound, and a use of the compound.

[0002]

BACKGROUND OF THE INVENTION The seaweed Ayanishiki (Martensia f.
An indole compound (maltefurazine A) represented by the following formula and isolated from an extract of C. ragilis Harvey) is publicly known [Summary of the 116th Annual Meeting of the Pharmaceutical Society of Japan, 2, 215 (1996)].

Embedded image And the said indole compound has an antioxidant effect,
It is known to have uses such as pharmaceuticals. The present inventors have established a method for synthesizing a stereoisomer of the indole compound and clarified its physiological activity for the purpose of elucidating the three-dimensional structure of the above-mentioned indole compound, its physiological activity and mechanism of action ( Japanese Patent Application No. 9-241417. The synthesis method is the following L-tryptophan (2A) and stereoisomer α
-Shown in the route to synthesize amino acid (3A) as intermediate.

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The present inventors aimed at searching for a compound having a stronger physiological activity than the compound of the above (1A) by using various α-amino acids and derivatives thereof corresponding to the above (3A). Many compounds were obtained according to the route. As a result, the compound of the above (1) corresponding to the deamino form of malteflazine A, which is the compound of (1A), has four isomers of malteflazine A, ie, (1 ″ S,
3 "S", (1 "R, 3" S), (1 "R, 3"
R) -form and (1 "S, 3" R) -form were found to have a higher lipid peroxidation inhibitory action.

[0004]

That is, the present invention relates to an indole compound represented by the following formula (1) or a salt thereof.

Embedded image [Wherein, R represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom,
Represents an amine or ammonium. ]

The present invention also provides the following formula (2)

Embedded image The tryptophan represented by the following formula (3)

Embedded image With a carboxylic acid represented by the following formula (4)

Embedded image Is obtained, and the compound of the formula (4) is cyclized to give the following formula (1)

Embedded image And a method for producing an indole compound represented by the formula:
[In the above formula, R represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom, an amine or ammonium. ]

Further, the present invention relates to a lipid peroxidation inhibitor comprising an indole compound represented by the above formula (1) or a salt thereof as an active ingredient.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the following description, the indole compound represented by the above formula (1) is also referred to as deaminomaltefurazine. In the compounds represented by the above formulas (1), (2) and (4), typical ones are those in which the group R is a hydrogen atom. Suitable substituents R other than hydrogen atoms are, in particular, linear or branched alkyl groups having 1 to 12, in particular 1 to 6, carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-. Butyl group,
Tertiary butyl group, pentyl group, hexyl group, octyl group,
Decyl and dodecyl groups; cycloalkyl groups having 5 to 6 ring carbon atoms, such as cyclopentyl group,
A methylcyclopentyl group, a cyclohexyl group and a methylcyclohexyl group; an aryl group having 6 to 16 carbon atoms and an aralkyl group having 7 to 16 carbon atoms,
For example, there are a phenyl group, a naphthyl group, a benzyl group and a phenylethyl group, and these groups may be substituted with a halogen atom, a hydroxy group, an alkoxy group, an amino group or the like. Further, the substituent R may be a monovalent metal such as sodium, potassium, amine or ammonium.

Examples of the salt of the compound of the formula (1) include an inorganic acid salt and an organic acid salt, and a hydrochloride is particularly preferable. The indole compounds of the present invention have an asymmetric carbon atom at the 3 "position. Accordingly, the compounds of the present invention include the two isomers, S-type and R-type, and mixtures of such isomers.

In the present invention, an amide represented by the formula (4) is formed by condensing tryptophan represented by the formula (2) with 4-methylhexanoic acid represented by the formula (3). According to a synthesis method in which an oxazole ring is constructed at once by oxidative cyclization of the amide compound, the compound of the formula (1)
To produce an indole compound represented by the formula: In addition, the oxidative cyclization reaction of the amide is particularly effective in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), whereby the cyclization proceeds efficiently, and the cyclized product is produced in high yield. can get.

In the compound represented by the formula (1) of the present invention, the substituent R may be determined by selecting the ester group of the starting tryptophan ester or by changing the substituent of the compound after synthesis to another substituent different from it. By converting to R, many types of compounds can be obtained.

The novel indole compound of the present invention is an alkaloid having an indole ring and an oxazole ring,
Has lipid peroxidation inhibitory activity, circulatory disorders such as arteriosclerosis, hypertension, thrombosis, inflammation such as nephritis, liver disorders such as alcoholic hepatitis, digestive disorders such as gastric ulcer, diabetes, carcinogenesis and aging, and other ultraviolet rays It can be used in cosmetic materials and the like as a preventive and therapeutic agent for disorders and the like, and as a preventive agent for ultraviolet rays.

[0012]

The synthesis scheme and production example of the indole compound of the present invention will be described. In the following description, the indole compound represented by the formula (1) is shown as compounds 12 and 13, the tryptophan represented by the formula (2) is shown as a compound 10, and 4-methylhexanoic acid represented by the formula (3) Is shown as compound S-6 and R-9, and the amide compound represented by formula (4) is shown as compound 11. Example 1 Synthesis of 4-methylhexanoic acid Production Example 1 : Optically active (S) -4-methylhexanoic acid (S
Synthesis of -6) Optically active (S) -4-methylhexanoic acid can be synthesized using optically active methylbutanol as a starting material. Scheme 1: Optically active (S) -4-methylhexanoic acid
Synthetic route

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[0013] 1. Tosylation of optically active methylbutanol
(Step 1 of Scheme 1) In a 100 ml eggplant-shaped flask, under an argon atmosphere,
(S) -2-methyl-1 butanol: 1 g (11.3 mmol) of (S) -1 (Tokyo Kasei) and anhydrous pyridine 3
After adding 0 ml and stirring at 0 ° C., 4.31 g (22.6 mmol) of p-toluenesulfonyl chloride was added.
After stirring at 30 ° C. for 30 minutes, the mixture is stirred at room temperature for 5 hours. Add ice water, adjust the pH of the aqueous layer to 2 to 3 with 3N hydrochloric acid, and extract with diethyl ether. After washing with a saturated aqueous solution of sodium bicarbonate and saturated saline, the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oil. This was subjected to column chromatography (75 g of SiO ₂ , hexane / ethyl acetate = 10: 1).
Then, 2.5 g of a tosyl compound (S) -2 (colorless oily substance: yield: 91.4%) was obtained. C ₁₂ H ₁₈ SO ₃ (MW. 242.10), colorless oil,
[Α] _D ²⁰ +5.66 (C = 1.060, MeOH)

[0014] 2. Iodination of Tosyl Form (S) -2
Step 2) of Tome 1) 1.94 g (8 mmol) of tosyl compound (S) -2 and 30 ml of anhydrous acetone were added to a 100 ml eggplant-shaped flask under an Ar atmosphere, and after shielding from light, sodium iodide 2.4 was added.
g (16 mmol) are added. After stirring for 2 days at room temperature, pentane is added to dilute the reaction solution, which is cooled to precipitate a sodium salt. After removing the sodium salt with a glass filter, the mixture was extracted with water to remove acetone, dried over anhydrous magnesium sulfate, and pentane was removed by distillation under normal pressure to obtain 1.08 g of an iodide (S) -3 (yield: 68. 0%). The structure was confirmed by comparison with a commercially available product.

[0015] 3. Malonic acid using iodine (S) -3
Ester Synthesis (Step 3 of Scheme 1) 1.38 g of metallic sodium and 50 ml of absolute ethanol were added to a 200 ml three- necked flask at 0 ° C. in an Ar atmosphere and stirred. When all the sodium is dissolved, 9.45 ml of diethyl malonate is added dropwise with a syringe, then 6.5 ml of iodine (S) -3 is added dropwise and stirred at room temperature overnight. 100 ml of an ammonium chloride aqueous solution is added, ethanol is removed by distillation under reduced pressure, and the residue is extracted with diethyl ether. The ether layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oil. This was subjected to column chromatography (SiO ₂ for flash 200 g, hexane / ethyl acetate = 30:
Purification in 1) gives 8.80 g of diester (S) -4.
(76.5% yield). C ₁₂ H ₂₂ O ₄ (MW 230.15), colorless oil,
[Α] _D ²⁰ +15.3 (C = 1.060, MeOH)

[0016] 4. Hydrolysis of diester (S) -4
(Step 4 of Scheme 1 ) 6.90 g of diester (S) -4 and 20 ml of ethanol are added to a 300 ml eggplant-shaped flask and stirred. 5.7 potassium hydroxide previously dissolved in 100 ml of water
1 g (102 mmol) is added and heated to reflux. The reaction solution is returned to room temperature, ethanol is removed by distillation under reduced pressure, and the residue is extracted with ethyl acetate to remove impurities. After adding 3N HCl to the aqueous layer to adjust the pH to 1 to 2, the mixture is extracted with ethyl acetate. The organic layer is salted out with sodium chloride, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure to obtain the desired dicarboxylic acid (S)-.
5.2 were obtained (yield 100%). C ₈ H ₁₄ O ₄ (MW. 174.09), white powder,
[Α] _D ²⁶ +16.9 (C = 1.10, MeOH)

[0017] 5. Decarboxylation of dicarboxylic acid (S) -5
Step 5 of Chime 1 5.05 g (29 mmol) of dicarboxylic acid (S) -5 in a 50 ml eggplant-shaped flask, a 7% aqueous solution of DMSO 16
ml and 1.87 g (32 mmol) of sodium chloride, and the mixture was heated at 150 to 175 ° C for 4 hours. The reaction solution was returned to room temperature, extracted twice with diethyl ether, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a colorless oil. This was purified by column chromatography (120 g of SiO ₂ , pentane / diethyl ether = 5: 1) to obtain 2.82 g of the desired carboxylic acid (S) -6 (yield: 75%). C ₇ H ₁₄ O ₂ (MW 130.10), colorless oil,
[Α] _D ²⁶ +9.69 (C = 1.042, MeOH)

Production Example 2 : Synthesis of optically active (R) -4-methylhexanoic acid (R-9) Optically active (R) -4-methylhexanoic acid is synthesized using (S) -citronellol as a starting material. . Scheme 2: Optically active (R) -4-methylhexanoic acid
Synthetic route

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1. Mesylation of (S) -citronellol
(Step 1 of Scheme 2 ) 5 g (32.0 mmol) of (S) -citronellol, 180 ml of dichloromethane, 4.86 g of triethylamine (35.2 ) in a 500 ml three-necked flask under an argon atmosphere.
mmol, 1.1 eq), and ice-cooled to −10 ° C., and then 4.03 g (35.2 mmol, 1.5.2 g) of mesyl chloride.
1 eq) is added dropwise. After stirring at -10 to 0 ° C (2.5 hours, the reaction solution was washed with ice water, 5% hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oil (S) -7. The following reduction reaction was carried out without purification.

[0020] 2. Reduction of Mesyl Form (S) -7 (Scheme
Step 2 of 2) A 200 ml three-necked flask was equipped with a salt tube and a reflux condenser, 400 ml of diethyl ether and 1.80 g of lithium aluminum hydride (47.3 mmol, 1.4 eq).
And cool on ice. (S) -7 7.92 g (33.8 m
mol) is added dropwise, and the mixture is refluxed for 3 hours. After completion of the reaction, the reaction solution was ice-cooled, and water3.
6 ml was added for 1 hour, and a 10% aqueous sodium hydroxide solution (2.88 ml) was further added. The mixture was stirred for 1 hour, and then filtered through celite to remove lithium aluminum hydride. The solvent was distilled off under reduced pressure to give a colorless oil (R) -8. Is 4.5 g (98
%) Obtained.

[0021] 3. Oxidation reaction of (R) -8 (of scheme 2
Step 3) 24.7 g (115.6 mmol, 3.6) of sodium periodate was placed in a 500 ml three-neck flask under an argon atmosphere.
eq), 175 ml of acetone aqueous solution (acetone: water = 7)
0: 105) and suspend. (R) -8 4.5
g (32.1 mmol) acetone solution was added dropwise,
Bring to 5 ° C. 0.86 g of potassium permanganate (5.4
6 mmol, 0.17 eq) 40 ml of an aqueous solution and 40 ml of acetone are simultaneously added dropwise. Stir at 5 ° C to room temperature for 20 hours. Celite filtration to remove reddish brown residue,
The acetone is distilled off by atmospheric distillation. The residue was made basic with 1N sodium hydroxide and extracted with diethyl ether to remove soluble matter. The aqueous layer was acidified with 3N hydrochloric acid, extracted with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oil. This was purified by column chromatography (SiO ₂ 50 g, hexane / ethyl acetate = 5: 1) to give (R) -9 as 2.
389 g (57%) were obtained.

(S) -4-Methylhexanoic acid can be produced in the same manner as in Production Example 2 when (R) -citronellol is used as a starting material.

Next, tryptophan ester (compound 1)
0) and 4-methylhexanoic acid (Compound S-6) from the indole compound deaminomaltefurazine (Compound 12,
13) shows a synthesis example. Example 2 Synthesis Scheme of Deaminomaltefurazine Scheme 3: Synthesis Route of Deaminomaltefurazine

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1. Synthesis of Compound 11 L-tryptophan benzyl ester hydrochloride (2.31
g, 7.0 mmol) in a THF (100 ml) solution, (S) -4-methylhexanoic acid (1.0 g, 1.1 equivalents), diethylphosphoryl cyanide (DEPC, 2.0
7 ml, 2.0 equivalents) and stirred at 0 ° C.
Triethylamine (2.34 ml, 2.4 equivalents) was added, and the mixture was further stirred at 0 ° C for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue. A saturated sodium bicarbonate solution was added to the ethyl acetate solution for washing, and then further washed with 10% hydrochloric acid and saturated saline. After drying the organic layer using anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
A crude product was obtained. The crude product was recrystallized from a mixed solvent of ethyl acetate: n-hexane (1: 1) to give compound 11 (2.5
4g, 89% yield).

Embedded image _{C 25 H 30 N 2 O 3} (MW.406.23); colorless powder;
80-81 ° C (ethyl acetate: n-hexane, 1:
1) [α] _D ²³ : −5.03 (c = 1.09, CHC
l ₃ ) IR (neat): ν [cm ⁻¹ ] 3300 (-NH), 31
12, 2959, 1732 (-COO), 1651 (-
CONH), 1519, 1456, 1379, 135
4,741,697 ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.5
9 (1H, broad, 1N-H), 7.53 (1H,
d, J = 7.8, 7-H), 7.21 (9H, m, aromatic H), 6.74 (1H, d, J = 1.7, 2-H),
6.12 (1H, d, J = 7.8, 1 ″ N−H);
09 (2H, dd, J = 12.2, 19.5, 4'-
H), 5.03 (1H, m, 2'-H), 3.32 (2
H, dd, J = 2.0, 5.4, 1'-H), 2.13
(2H, m, 3 "-H), 1.61 (1H, m, 4"-
H), 1.38 (1H, m, 4 "-H), 1.29 (2
H, m, 6 "-H), 1.10 (1H, m, 5"-
H), 0.84 (3H, d, J = 7.1, 8 "-H),
0.82 (3H, t, J = 6.2, 7 "-H)

[0025] 2. Compound 12 [Formula wherein R is a benzyl group
Compound (1) (500 mg, 1.23 mmol) of THF
(50 ml), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 698 mg, 2.5 equivalents) was added, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, water was added, and THF was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue for extraction. The organic layer was washed with a saturated sodium hydrogen carbonate solution and further with a saturated saline solution, and then dried using anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate: n-hexane, 1: 5).
Almost pure compound 12 was obtained (232 g, yield 47).
%). Compound 12 was further recrystallized from ethyl acetate.

Embedded image _{C 25 H 26 N 2 O 3} (MW.402.19); colorless powder;
138.5-139.5 ° C. (ethyl acetate) [α] _D ²³ : +7.14 (c = 1.00, CHC
l ₃ ) IR (neat): ν [cm ⁻¹ ] 3323, 2960, 16
84 (CO), 1604, 1570, 1280, 124
6,1203,1140,1076,785,746 ¹ H-NMR (400 MHz, CDCl ₃ ): δ8.7
1 (1H, d, J = 2.9, 2'-H), 8.59 (1
H, broad, 1N-H), 8.18-8.13 (1
H, m, 7'-H), 7.45 (3H, m, 4 ',
5 ', 6'-H), 7.31 (5H, m, -Ph),
_{5.43 (2H, s, -CH 2} Ph), 2.92 (2
H, m, 1 "-H), 1.93 (1H, m, 2"-)
H), 1.71 (1H, m, 2 "-H), 1.45 (2
H, m, 4 "-H), 1.23 (1H, m, 3"-
H), 0.96 (3H, d, J = 6.5, 6 "-H),
0.91 (3H, t, J = 7.3, 5 "-H)

[0026] 3. Compound 13 [in the formula (1) wherein R is H
Compound represented by an indole compound] 12 (100mg, 0.25mmol) was dissolved in ethyl acetate 10 ml, 10% palladium on carbon 100m
g was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After adding ethanol to the reaction solution and filtering the catalyst, the filtrate was concentrated under reduced pressure, and the obtained crude product (95.4 mg) was subjected to column chromatography (silica gel, ethyl acetate: methanol, 10: 1). Purification gave compound 13 (53 mg, 69% yield).

Embedded image _{C 18 H 20 N 2 O 3} (MW.312.15); colorless powder;
Melting point: 181.0-183.0 ° C. (water-containing ethanol) IR (neat): ν [cm ⁻¹ ] 3161, 960, 16
76, 1603, 1560, 1458, 1414, 12
^{78,1130,1082,949,741 1 H-NMR (400MHz,} CDCl 3): δ8.6
4 (1H, s, 2'-H), 8.04 (1H, d, J =
8.0, 7'-H), 7.42 (1H, d, J = 7.
3,4'-H), 7.20-7.13 (2H, m, 5 '
And 6'-H), 2.88-2.74 (2H, m, 1 ").
-H), 1.90-1.80 (1H, m, 2 "-H),
1.66-1.57 (1H, m, 2 "-H), 1.45
-1.34 (2H, m, 4 "-H), 1.25-1.1
3 (1H, m, 3 ″ -H), 0.92 (3H, d, J =
6.6, 6 "-H), 0.87 (3H, t, J = 7.
2,5 ″ -H)

Example 3 Effect of Indole Compound on Lipid Peroxidation of Rat Liver Microsomes (1) Measurement of Lipid Peroxide In 0.5 ml of 0.1 M Tris-HCl buffer (pH 7.5) containing 14 mM MgCl _2. Microsomal fraction prepared from rat liver (protein concentration 30-50 mg / ml)
10 μl and 10 μl of an ethanol solution of the test compound were added, mixed, and pre-incubated at 37 ° C. for 5 minutes. Next, 10 μl of 0.2 M adenosine diphosphate, 12 mM
10 μl of FeSO ₄ , 40 μl of NADPH regeneration system and distilled water were added to make 1 ml, mixed, and reacted at 37 ° C. for 10 minutes. After the reaction, 2 ml of a 15% trichloroacetic acid solution containing 0.375% thiobarbituric acid (TBA) and 0.25N hydrochloric acid was added and reacted in a boiling water bath for 15 minutes, and malondialdehyde produced by this reaction was added. The amount of the thiobarbituric acid-reactive substance to be
The absorbance at 5 nm was measured and determined. Based on this value,
The value that suppresses lipid peroxidation by 50% (IC ₅₀ value) was determined.

(2) Test Results Deaminomaltefurazine (compound 13) of Example 2 and synthetic (1 ″ S, 3 ″ S) malteflazine A having the same structure as the natural form [of the compound of formula (1A) (1 "S, 3"
S))] were compared for their lipid peroxidation inhibitory activity. As a result, as shown in the table below, the IC ₅₀ values of deaminomaltefurazine and synthetic ((1 ″ S, 3 ″ S) malteflazine A were 0.33 μg / ml and 1.35 μg / ml, respectively. Aminomaltefurazine showed stronger activity.

[0029]

Industrial Applicability The novel amide compound is formed by condensation of tryptophan and 4-methylhexanoic acid of the present invention, and the oxazole ring is simultaneously formed by an oxidative cyclization reaction of the amide compound. It has become possible to obtain indole compounds. The obtained alkaloid having an indole ring and an oxazole ring has a higher physiological activity such as a lipid peroxidation inhibitory activity as compared with the known compound maltefurazine A, and can be used for pharmaceuticals and cosmetic materials.

Claims (4)

[Claims] 1. An indole compound represented by the following formula (1) or a salt thereof. Embedded image [Wherein, R represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom,
Represents an amine or ammonium. ] 2. The indole compound according to claim 1, wherein R represents a hydrogen atom, or a salt thereof. 3. The following formula (2): The tryptophan represented by the following formula (3) And condensed with a carboxylic acid represented by the following formula (4): Is obtained, and the compound of the formula (4) is cyclized to give the following formula (1): A method for producing an indole compound represented by the formula: [In the above formula, R represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom, an amine or ammonium. ] 4. A lipid peroxidation inhibitor comprising the indole compound according to claim 1 or a salt thereof as an active ingredient.